rs1161932777

Positions:

• chr16-1772798-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_023936.2(MRPS34):​c.321+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000658 in 151,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
• Consequence: MRPS34 NM_023936.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.39

Genes affected

MRPS34 (HGNC:16618): (mitochondrial ribosomal protein S34) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.5098935 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1772798-C-A is Pathogenic according to our data. Variant chr16-1772798-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 430586.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-1772798-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS34	NM_023936.2	c.321+1G>T		splice_donor_variant, intron_variant		ENST00000397375.7	NP_076425.1
MRPS34	NM_001300900.2	c.321+1G>T		splice_donor_variant, intron_variant			NP_001287829.1
EME2	NM_001257370.2	c.-430C>A		upstream_gene_variant		ENST00000568449.7	NP_001244299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS34	ENST00000397375.7	c.321+1G>T		splice_donor_variant, intron_variant		1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.321+1G>T		splice_donor_variant, intron_variant		1		ENSP00000177742.3
EME2	ENST00000568449.7	c.-430C>A		upstream_gene_variant		1	NM_001257370.2	ENSP00000457353.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151940 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 63

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151940 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 74192

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Leigh syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Mitochondrial Research Group, Murdoch Children's Research Institute

Jun 29, 2017

- -

Combined oxidative phosphorylation deficiency 32 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: 25
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1161932777; hg19: chr16-1822799;